Registration Dossier

Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
27.04 - 28.06.1982
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1982
Report Date:
1982

Materials and methods

Principles of method if other than guideline:
The objective of the study was to determine the acute median lethal dosage after a single oral administration to rats.
After acclimatization, the animals were deprived of food before admistration of the test sample. The animals were doses orally by a stomach tube and observed for 14 days in which clinical examination and body weight follow-up was done. At autopsy the gross pathology was evaluated.
GLP compliance:
not specified
Test type:
standard acute method
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
rat
Strain:
other: BOR: WISW, SPF TNO
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Firma Winkelmann, Versuchstierzucht, 4791 Borchen 1, Gartenstraße 300
- Weight at study initiation: males: 179.0 - 194.6 g; females: 137.5 - 165.1 g
- Housing: collection caging; Makrolon type III/ max. 5 rats + Ssniff bedding
- Fasting period before study: 16 hours
- Diet: ad libitum; pellets
- Water: ad libitum; Makrolon drinking bottles, 300 ml
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 +/- 2
- Humidity (%): 45- 55
- Photoperiod (hrs dark / hrs light): 12 hours daily, from 7.00 a.m. - 19.00 p.m.
- lighting: flourescent light, 120 Lux

IN-LIFE DATES: 27.04.1982 - 17.05.1982

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: Oleum arachidis
Details on oral exposure:
DOSAGE PREPARATION: 15 % (R.F. 50 %, 15 %) solution in Oleum arachidis. The pH-value of the liquid was 5,9.
APPLICATION: stomach tube
RANGE FINDING STUDY: 5 pairs of 2 female rats: 10.0, 5.0, 2.5, 1.0 and 0.5 g/kg bw.
Doses:
500, 750, 1000 and 1500 mg/kg bw
No. of animals per sex per dose:
10
Control animals:
no
Details on study design:
- Preparation of animals: animals were deprived of food for 16h
- Duration of observation period following administration: 14 days
- Clinical observation: a modified Irvin-Screening; ca.10 min , 30 min and 1 h , 3 h , 24 h , 48 h , 72 h , 7 and 14 days.
- Frequency of observations and weighing: day 0 and day 14
- Necropsy of survivors performed: yes
Statistics:
- Randomization: lottery drawing
- Calculation of the oral LD50

Results and discussion

Preliminary study:
The range finding study showed that all treated animals of the dosages 10, 5 and 2.5 g/kg died within 24 h. At the dosage of 1 g/kg 1 animal died 24 h. At the dosage of 0,5 g/kg no mortality was observed.
Effect levels
Sex:
male/female
Dose descriptor:
LD50
Effect level:
730 mg/kg bw
Based on:
test mat.
Remarks on result:
other: mean value males and females
Mortality:
During 24 h all 10 animals died at the dosage of 1.5 g/kg. At dose 1 g/kg 6 animals died within 24 h and altogether 9 animals of 10 treated within 3 days. At the dosage of 0.75 g/kg 1 animal died within 24 h and after 3 days 5 out of 10 treated animals. At the dosage of 0.5 g/kg 1 animal died within 48 h.
Clinical signs:
The substance induced an increase in restlessness, slight stereotypy and irritability, pointing to an excitation stage which was followed by partly complete apathia (similar to narcosis). Above the severe abnormal body posture, obvious disturbance of coordination, partly obvious reduced reflex excitability, slight decreased respiration rate and slight to obvious hyperemia was observed. The latter transformed after 3 h partly into a slight cyanosis. The symptoms described hold on in the animals dying in the same severe intensity until death. The surviving animals showed this in decreased intensity up to 48 h. Afterwards and during the remaining observation period the animals showed a normal disposition.
Body weight:
Body weight changes of the surviving animals after the observation period showed a normal weight gain.
Gross pathology:
The animals that died during the study showed at autopsy slight to obvious redness of the whole digestive systems. Nothing abnormal was found in the animals necropsied on day 14.

Applicant's summary and conclusion

Interpretation of results:
Toxicity Category IV
Remarks:
Criteria used for interpretation of results: EU
Conclusions:
The acute oral LD50 was determined to be 790 mg/kg for male rats and 640 mg/kg for female rats. The mean LD50 was 730 mg/kg.
Executive summary:

In the current study the acute oral toxicity was investigated after a single oral administration of the test item. Four groups of fasted male and female rats of the WISW-strain rats were dosed by a stomach tube. 
Any signs of reaction and mortalities were recorded during the 14-days observation period, animals that died and those that were killed at the end of the study were subjected to necropsy. 


The doses tested were 0.5, 0.75, 1.0 and 1.5 g/kg

The test item affected the awareness and coordination. Moreover, the animals showed an abnormal body posture and reduced reflex excitability. Also, a decrease in respiration rate was observed, as well as hyperemia and cyanosis.


The post-dosing weight gains of the surviving animals were not essentially different after 2 weeks.


The animals that died during the study showed a slight to obvious redness of the whole digestive system. 
No abnormalities were found in the animals necropsied at day 14. 


 

The mortality rates were:

Dose (mg/kg)

Mortality rate

1500

10/10

1000

9/10

750

5/10

500

1/10

 

The acute oral LD50 was determined to be 790 mg/kg for male rats and 640 mg/kg for female rats. The mean LD50 was 730 mg/kg.